Mint mask and methods of use thereof

ABSTRACT

Provided are methods and devices useful for treating a respiratory disease or disorder involving the central or upper airways. The methods and devices deliver to central or upper airways of a subject a vapor or aerosol comprising an effective amount of an active ingredient selected from the group consisting of menthol, menthone, neomenthol, isomenthol, and menthofuran. The methods are useful for treating conditions including cough, asthma, bronchitis, and allergic rhinitis.

RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.15/689,332, filed Aug. 29, 2017, which claims the benefit of priority toU.S. Provisional Patent Application Ser. No. 62/381,270, filed Aug. 30,2016, the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Along with vanilla and chocolate, peppermint is one of the most commonflavorings in the world, and it is widely used to flavor confectionery,chewing gum, desserts, oral hygiene products, and many other products.In addition to being a benign and ubiquitous flavoring, peppermint isalso a potent antispasmodic phytomedicine that relaxes smooth muscles inmany instances. The main constituents of volatile oil of peppermint arethe cyclic terpene alcohol (−)-menthol (C₁₀H₂₀O, MW 156.27) (35-55%) andits stereoisomers menthone (10-40%), (+)-neomenthol (about 3%), and (+)isomenthol (3%). Menthol is the most prevalent and most studiedconstituent, but other components may contribute to the effect ofpeppermint oil.

Asthma is a common chronic lung disorder in which inflammation causesthe bronchi to swell and narrow the airways, creating breathingdifficulties that may range from mild to life-threatening. Symptomsinclude acute episodes of shortness of breath, cough, wheezing, andchest tightness lasting minutes to hours, even to days. Approximately 5percent of the population of the United States is affected. Currenttreatments typically include beta-adrenergic agonists, methylxanthines,anticholinergics, and anti-inflammatory agents such as glucocorticoids.Beta-adrenergic agonists and anticholinergics typically are administeredas aerosols, whereas methylxanthines and glucocorticoids are typicallyadministered orally or intravenously; glucocorticoids are sometimesadministered as aerosols.

Bronchitis is a common lung disorder associated with excessivetracheobronchial mucus production with cough with expectoration. Chronicbronchitis is a common chronic lung disorder associated with excessivetracheobronchial mucus production sufficient to cause cough withexpectoration for at least three months of the year for more than twoconsecutive years. A subset of patients with chronic bronchitis haveclinically significant airway obstruction accompanied by severe dyspnea(air hunger) and wheezing in association with inhaled irritants orduring acute respiratory infections. Current treatments typicallyinclude beta-adrenergic agonists, methylxanthines, anticholinergics, andantibiotics. Beta-adrenergic agonists and anticholinergics typically areadministered as aerosols, whereas methylxanthines and glucocorticoidsare typically administered orally or intravenously; glucocorticoids aresometimes administered as aerosols.

A need still exists for effective, accessible treatments for these andother respiratory diseases and disorders.

SUMMARY OF THE INVENTION

The invention provides a phytomedicine delivery device and relatedmethods useful to treat asthma, allergic rhinitis, bronchitis,respiratory infections, cough, and wheezing. The delivery device, whichcan be made of simple, easily obtainable, inexpensive materials, isdesigned to be portable, disposable, inexpensive, biodegradable, andsuitable to be sold over-the-counter. In certain embodiments, thedelivery device and methods of the invention comprise a simplemechanical rebreathing device and a pharmacologically activephytomedicine, volatile oil of peppermint. In certain embodiments, thedevice can be breath-activated. In certain embodiments, the devicedelivers therapeutic levels of two bronchodilating agents: menthol andrelated compounds from the peppermint oil, and carbon dioxide fromtrapped exhalations.

An aspect of the invention is a method of treating a respiratory diseaseor disorder involving the central airways, comprising administering tothe central airways of a subject in need thereof a vapor or aerosolcomprising a therapeutically effective amount of an activepharmaceutical ingredient (API) selected from the group consisting ofmenthol, menthone, neomenthol, isomenthol, menthofuran, and anycombination thereof.

In certain embodiments, the API comprises menthol.

In certain embodiments, the API is provided as volatile oil ofpeppermint.

In certain embodiments, the vapor or aerosol is a vapor.

In certain embodiments, the vapor or aerosol is an aerosol.

In certain embodiments, the API is administered in conjunction with arebreathing device.

In certain embodiments, the rebreathing device comprises a semi-poroussubstrate impregnated with the API.

In certain embodiments, the rebreathing device is a mask comprising asemi-porous substrate impregnated with the API, and the mask isconstructed and arranged to fit over nose, mouth, or both nose and mouthof the subject.

In certain embodiments, the rebreathing device is breath-activated.

In certain embodiments, the vapor or aerosol is delivered to the centralairways by inhalation by the subject.

In certain embodiments, the respiratory disease or disorder involvingthe central airways is bronchitis.

In certain embodiments, the respiratory disease or disorder involvingthe central airways is respiratory infection involving the centralairways.

In certain embodiments, the method treats cough.

In certain embodiments, the method treats wheezing.

In certain embodiments, the subject is a human.

An aspect of the invention is a method of treating allergic rhinitis,comprising administering to the upper airways of a subject in needthereof a vapor or aerosol comprising a therapeutically effective amountof an API selected from the group consisting of menthol, menthone,neomenthol, isomenthol, menthofuran, and any combination thereof,wherein the API is administered in conjunction with a rebreathingdevice.

An aspect of the invention is a method of treating cough, comprisingadministering to the airways of a subject in need thereof a vapor oraerosol comprising a therapeutically effective amount of an API selectedfrom the group consisting of menthol, menthone, neomenthol, isomenthol,menthofuran, and any combination thereof, wherein the API isadministered in conjunction with a rebreathing device.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an embodiment of the rebreathing device.

FIG. 2 depicts a subject using a rebreathing device covering the nose.

FIG. 3 depicts a subject using a rebreathing device covering both thenose and mouth.

DETAILED DESCRIPTION OF THE INVENTION

Active Pharmaceutical Ingredient (API)

Oil of peppermint has proven medical applications, primarily because ofits antispasmodic effects on smooth muscle. Therapeutically, an oralpreparation of volatile oil of peppermint oil has proven beneficial forirritable bowel syndrome in many randomized controlled trials. Khanna etal., J. Clin. Gastroenterol. 48: 505-12 (2014). Instilled preparationsreduce spasm after colonoscopy (Shavakhi et al., Nihon Rinsho 68:2126-34 (2010)), endoscopic retrograde cholangiopancreatography (ERCP;Yamamoto et al., J. Gastroenterol Hepatol. 21: 1394-8 (2006)), andduring upper gastrointestinal endoscopy (Fujishiro et al., J.Gastroentrol. 49: 446-54 (2014); Hiki et al., Dig. Endosc. 24: 79-86(2012)).

Few studies have been conducted on the effects of peppermint or mentholon the respiratory tract; most of these studies have focused on thenasal airway, for which results are not impressive. A recent randomizedcrossover trial in ten normal subjects found no effect of inhaledmenthol on upper airway resistance. Pereira et al., Can. Respir. J. 20:e1-4 (2013).

Nevertheless, menthol is a common ingredient in cough and cold products,usually in decongestant preparations, although several studies haveshown that menthol has no effect on nasal resistance. For example,menthol is an ingredient in Vicks VapoRub, an over-the-counter ointmentindicated for topical use on the chest, back, and throat for coughsuppression due to the common cold or on muscles and joints for minoraches and pains. Vicks VapoRub also contains camphor and eucalyptus oil,which also act as cough suppressants.

Menthol is also a common additive in cigarettes; 90% of marketedcigarettes contain menthol, including many that are not marketed asmenthol cigarettes.

In guinea pigs, menthol has antitussive (cough suppressant) effects(Laude et al., Pulm. Pharmacol. 7: 179-84 (1994) and attenuatescapsaicin- and neurokinin A-induced bronchoconstriction (Wright et al.,Br. J. Pharmacol. 121: 1645-50 (1997)). Menthol inhibits bronchialcontraction due to methacholine and high extracellular potassium;inhibition of calcium influx is important in menthol-mediated inhibitionof smooth muscle contraction in airways. Ito et al., Pulm. Pharmacol.Ther. 21: 812-7 (2008). Other experiments have shown that mentholrelaxes bronchi preconstricted with acetylcholine or potassium chloride,and has surfactant effects, lowering surface tension on bronchialsurfaces. Additionally, menthol may prolong breath holding. Mentholvapor reduces reactivity to chemical irritants (Wise et al., NicotineTob. Res. 13: 989-97 (2011)) including acrolein, acetic acid, andcyclohexanone (Willis et al., FASEB J. 25: 4434-44 (2011)).

The mammalian transient receptor potential (TRP) cation channels aredivided based on sequence homology into six categories: TRPC(canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPP(polycystin), and TRPML (mucolipin). These channels are activated bymany chemical and physical stimuli and appear to be important in variousrespiratory diseases including asthma and chronic obstructive pulmonarydisease (COPD). Banner et al., Pharmacol. Ther. 130: 371-84 (2011).Menthol interacts with transient receptor potential melastatin 8(TRPM8), present in cold-sensitive sensory neurons, and transientreceptor potential ankyrin 1 (TRPA 1), an irritant-sensing channel.

Menthol, which is thought to have decongestant properties although itdoes not, is not used or marketed for bronchitis or asthma. Two of threestudies have found a benefit of menthol and cough. Menthol inhalation inpatients with chronic cough reduced cough sensitivity to inhaledcapsaicin and had an effect on inspiratory flows. Millqvist et al.,Respir. Med. 107: 43-8 (2013). Menthol vapor and the taste of sucrosealso reduced cough reflex to capsaicin challenge in another study. Wiseet al., Pulm. Pharmacol. Ther. 25: 236-41 (2012). Another clinical studyfound no effect of premedication with 1% menthol inhalation on coughafter fiberoptic bronchoscopy. Haidl et al., Pneumologie 55: 115-9(2001).

There is only one published study on the use of menthol to treat asthma.In a study of 23 asthmatics, 4 weeks of nebulized menthol (10 mg twicedaily for four weeks) decreased diurnal variation in peak expiratoryflow rate (PEFR), a measure of airway excitability, reduced wheezingepisodes, and reduced use of metered dose inhalers. The treatment had noeffect on VC (vital capacity) or FEV₁ (forced expiratory volume at 1second). Menthol may reduce airway hyperresponsiveness without changingthe magnitude of airflow limitation. Tamaoki et al., Resp. A Med. 89:503-4 (1995).

Peppermint oil (oil of peppermint) is readily available from a number ofcommercial suppliers. It is volatile at room temperature.

Menthol ((1R,2S,5R)-2-Isopropyl-5-methylcyclohexanol) is readilyavailable from a number of commercial suppliers; it is typicallypresented either as waxy crystals or as an oil. The main form of mentholoccurring in nature is (−)-menthol, which is assigned the (1R,2S,4R)configuration. Menthol is manufactured as a single enantiomer(1R,2S,5R-menthol; 94% ee) on the scale of 3,000 tons per year byTakasago International Corporation. The process involves an asymmetricsynthesis developed by a team led by Ryōji Noyori, who won the 2001Nobel Prize for Chemistry in recognition of his work on this process.The process begins by forming an allylic amine from myrcene, whichundergoes asymmetric isomerization in the presence of a BINAP rhodiumcomplex to give (after hydrolysis) enantiomerically pure R-citronellal.This is cyclized by a carbonyl-ene-reaction initiated by zinc bromide toisopulegol, which is then hydrogenated to give pure (1R,2S,5R)-menthol.

Rebreathing Device

Asthmatics often breathe faster as a way of compensating for airwayconstriction, but hyperventilation decreases carbon dioxide, therebyworsening the condition by causing lightheadedness, anxiety, andbronchoconstriction. Slow breathing not only relieves symptoms ofhyperventilation, but also has a beneficial effect on asthma. Asthmaticpatients can be trained in Buteyko breathing techniques, whichintersperse breath holding with periods of shallow, slow breathing.Buteyko breathing has been shown to be an effective treatment forasthmatics, but it requires effort and training on the part of thesubject.

Controlled breathing builds up carbon dioxide in the airways, dilatingsmooth muscles in the bronchi while maintaining a eucapnic state (i.e.,without increasing carbon dioxide in the blood). Prem et al., Clin.Rehabil. 27: 133-41 (2013). A number of studies have found that Buteykobreathing techniques reduce symptoms and medication use in asthmaticpatients. Compared to control and pranayama breathing, Buteyko breathingimproved Asthma Control Questionnaire scores at 3 months, improved FEV₁,and improved FEV₁/FVC (forced vital capacity). Prem et al., Clin.Rehabil. 27: 133-41 (2013).

A systematic review of 13 studies of asthmatic patients involving 906participants (11 compared breathing exercise with inactive control, andtwo with asthma education) found improvement in quality of life in alleight studies that assessed this and an improvement (reduction) in thenumber of acute exacerbations in the one study that assessed this. Sixof seven studies showed significant differences favoring breathingexercises for asthma symptoms. Effects on lung function were variable. Ameta-analysis of the two studies assessing changes in the Asthma Qualityof Life Questionnaire favored breathing exercises.

By having the user breathe into a semi-porous enclosed space, the deviceportion of the invention reproduces the beneficial effect of controlledbreathing without requiring any effort or training on the part of theuser. A semi-porous enclosed space provides plenty of oxygen and willnot make a person feel air hunger; the effect is similar to breathinginto a paper bag. Rebreathing also warms and humidifies air, which ishelpful in preventing cold-induced asthma.

In certain embodiments, the rebreathing device is a generally cup-,cone-, or beak-shaped mask comprising a semi-porous substrate material(paper, woven or non-woven cloth, cellulose, sponge, foam, other naturalfiber, or other synthetic material); for use, the semi-porous substratematerial is at least partially impregnated with volatile oil ofpeppermint (Mentha x piperita) or of other Mentha species, or one ormore of the major constituents of peppermint oil (e.g., menthol,menthone, or menthofuran). The mask will conformably cover the nose, orthe nose and mouth, with an adjustable band, strap or tie that encirclesthe head or hooks over the ears to hold the mask in place. In certainembodiments, the mask will also have a flexible band or other devicemade of plastic, metal, or another material to improve fit over thenose. In certain embodiments, the rebreathing device is similar to oressentially the same as a commercially available dust mask. In certainembodiments, the rebreathing device is similar to or essentially thesame as a commercially available surgical or medical mask.

For use, the volatile oil or constituent (API) is contacted with thedevice, or at least the semi-porous substrate material portion of thedevice, using any suitable method. In certain embodiments, the API issupplied with the mask in a container such as a small foil or plasticfilm or pouch with a tear-off strip that, when opened, exposes thecompound. In certain embodiments, the API is provided attached to themask in a small foil or plastic film or pouch with a tear-off stripthat, when opened, exposes the compound.

The rebreathing device is constructed and arranged so that the user canbreathe while wearing the device. That is, in certain embodiments, therebreathing device is constructed and arranged so that the user canbreathe through the mask.

In certain embodiments, the rebreathing device is generally a bag,inside of which is a semi-porous substrate material (paper, woven ornon-woven cloth, cellulose, sponge, foam, other natural fiber, or othersynthetic material); for use, the semi-porous substrate material is atleast partially impregnated with volatile oil of peppermint (Mentha xpiperita) or of other Mentha species, or one or more of the majorconstituents of peppermint oil (e.g., menthol, menthone, ormenthofuran). For use, the volatile oil or constituent (API) is appliedto the device or at least the semi-porous substrate material portion ofthe device using any suitable method. In certain embodiments, the API issupplied with the bag in a container such as a small foil or plasticfilm or pouch with a tear-off strip that, when opened, exposes thecompound. The user can breathe into the bag.

Other embodiments are also contemplated by the invention. For example,in certain embodiments, the rebreathing device is generally a rigid orsemi-rigid cylinder, comprising or inside of which is a semi-poroussubstrate material (paper, woven or non-woven cloth, cellulose, sponge,foam, other natural fiber, or other synthetic material); an open end ofthe cylinder is suitably sized to accommodate a user's nose or nose andmouth. For use, the semi-porous substrate material is at least partiallyimpregnated with volatile oil of peppermint (Mentha x piperita) or ofother Mentha species, or one or more of the major constituents ofpeppermint oil (e.g., menthol, menthone, or menthofuran). For use, thevolatile oil or constituent (API) is contacted with the device, or atleast the semi-porous substrate material portion of the device, usingany suitable method.

Methods

An aspect of the invention is a method of treating a respiratory diseaseor disorder involving the central airways, comprising administering tothe central airways of a subject in need thereof a vapor or aerosolcomprising a therapeutically effective amount of an activepharmaceutical ingredient (API) selected from the group consisting ofmenthol, menthone, neomenthol, isomenthol, menthofuran, and anycombination thereof.

As used herein, “treat” or “treating” refers to ameliorating at leastone sign or symptom of a disease or disorder in a subject. In certainembodiments, the improvement can be objectively measured. For example,in treating asthma, improvement may include improvement in forcedexpiratory volume in one second (FEV₁), peak expiratory flow rate(PEFR), or both. In certain embodiments, the improvement can besubjective. In certain embodiments, “treat” or “treating” refers tofully resolving at least one sign or symptom of a disease or disorder ina subject. In certain embodiments, “treat” or “treating” refers to fullyresolving a disease or disorder in a subject.

As used herein, “central airways” refers generally to the lowerrespiratory system, comprising larynx, trachea, bronchi, bronchioles,and alveoli. In certain embodiments, “central airways” refers toconducting airways of the lungs, i.e., trachea, bronchi, andbronchioles.

In certain embodiments, the vapor or aerosol is a vapor.

In certain embodiments, the vapor or aerosol is an aerosol.

A “respiratory disease or disorder involving central airways” refersgenerally to any inflammatory, allergic, irritant, or infectious diseaseor disorder involving central airways, or any combination thereof.

In certain embodiments, the respiratory disease or disorder involvingcentral airways is asthma. The asthma can be allergic, cold-induced,exercise-induced, irritant-induced, or idiopathic.

In certain embodiments, the respiratory disease or disorder involvingcentral airways is bronchitis. In certain embodiments, the bronchitis ischronic bronchitis.

In certain embodiments, the respiratory disease or disorder involvingcentral airways is a respiratory infection involving the centralairways, e.g., pneumonia or pneumonitis.

In certain embodiments, the method treats cough.

In certain embodiments, the method treats wheezing.

A “subject”, as used herein, refers to a mammal. In certain embodiments,the subject is a mouse, rat, guinea pig, rabbit, cat, dog, pig, sheep,goat, cow, horse, non-human primate, or a human.

In certain embodiments, the subject is a human.

In certain embodiments, the API comprises menthol. In certainembodiments, the API consists of menthol.

In certain embodiments, the API is provided as volatile oil ofpeppermint.

In accordance with each of the foregoing embodiments, in certainembodiments, the API is administered in conjunction with a rebreathingdevice. In certain embodiments, the rebreathing device comprises asemi-porous substrate that is at least partially impregnated with theAPI. In certain embodiments, the rebreathing device is a mask comprisinga semi-porous substrate that is at least partially impregnated with theAPI, and the mask is constructed and arranged to fit over the nose,mouth, or both the nose and mouth of the subject.

In certain embodiments, the rebreathing device is breath-activated. Thatis, the rebreathing device is activated by the subject breathingspontaneously through or into the rebreathing device, without assistanceof a mechanical ventilator. The simple act of inhalation entrains thevaporized or aerosolized API and delivers the vapor or aerosol,including in particular the API, to the central airways of the subject.

Additional details and embodiments in connection with the rebreathingdevice are provided above.

To operate the rebreathing device, a user or subject applies thevolatile oil or API to the semi-porous substrate, thereby activating therebreathing device. In certain embodiments, for this purpose thevolatile oil or API can be dissolved in alcohol or other suitablesolvent. The subject dons the activated rebreathing device (e.g., mask),adjusts the fit to his or her face, and breathes using the device for aperiod of time sufficient to achieve a desired effect. Typically, thisperiod of time will be about 1-30 minutes. In some embodiments, thisperiod of time will be about 1-20 minutes. In some embodiments, thisperiod of time will be about 1-15 minutes. In some embodiments, thisperiod of time will be about 1-10 minutes. In some embodiments, thisperiod of time will be about 1-5 minutes. In some embodiments, thisperiod of time will be about 1-2 minutes. In some embodiments, thisperiod of time will be about 2-30 minutes. In some embodiments, thisperiod of time will be about 2-20 minutes. In some embodiments, thisperiod of time will be about 2-15 minutes. In some embodiments, thisperiod of time will be about 2-10 minutes. In some embodiments, thisperiod of time will be about 2-5 minutes. In some embodiments, thisperiod of time will be about 5-30 minutes. In some embodiments, thisperiod of time will be about 5-20 minutes. In some embodiments, thisperiod of time will be about 5-15 minutes. In some embodiments, thisperiod of time will be about 5-10 minutes. In some embodiments, thisperiod of time will be about 10-30 minutes. In some embodiments, thisperiod of time will be about 10-20 minutes. The treatment can berepeated as needed.

In certain embodiments, the vapor or aerosol is delivered to the centralairways by inhalation by the subject. For example, the subject breathesspontaneously through or into the rebreathing device, without assistanceof a mechanical ventilator. The simple act of inhalation entrains thevaporized or aerosolized API and delivers the vapor or aerosol,including in particular the API, to the central airways of the subject.

An aspect of the invention is a method of treating allergic rhinitis,comprising administering to the upper airways of a subject in needthereof a vapor or aerosol comprising a therapeutically effective amountof an active pharmaceutical ingredient (API) selected from the groupconsisting of menthol, menthone, neomenthol, isomenthol, menthofuran,and any combination thereof, wherein the API is administered inconjunction with a rebreathing device.

Allergic rhinitis, also known as hayfever, is a common type ofinflammation in the nose which occurs when the immune system reacts toallergens in the air. Symptoms typically include sneezing, rhinorrhea,post-nasal drip, nasal obstruction, and nasal, conjunctival, andpharyngeal itching.

As used herein, “upper airways” refers to the nasal cavities andpharynx.

In certain embodiments, the API comprises menthol. In certainembodiments, the API consists of menthol.

In certain embodiments, the API is provided as volatile oil ofpeppermint.

In certain embodiments, the vapor or aerosol is a vapor.

In certain embodiments, the vapor or aerosol is an aerosol.

In certain embodiments, the rebreathing device and its operation are asdescribed above.

In certain embodiments, the rebreathing device is a mask comprising asemi-porous substrate impregnated with the API, and the mask isconstructed and arranged to fit over nose, mouth, or both nose and mouthof the subject.

In certain embodiments, the mask is constructed and arranged to fit overthe nose of the subject.

In certain embodiments, the rebreathing device is breath-activated.

In certain embodiments, the vapor or aerosol is delivered to the upperairways by inhalation by the subject.

In certain embodiments, the method treats cough.

In certain embodiments, the subject is a human.

An aspect of the invention is a method of treating cough, comprisingadministering to the airways of a subject in need thereof a vapor oraerosol comprising a therapeutically effective amount of an activepharmaceutical ingredient (API) selected from the group consisting ofmenthol, menthone, neomenthol, isomenthol, menthofuran, and anycombination thereof, wherein the API is administered in conjunction witha rebreathing device.

As used herein, “airways” refers to upper, central, and/or both upperand central airways as used herein.

In certain embodiments, the API comprises menthol. In certainembodiments, the API consists of menthol.

In certain embodiments, the API is provided as volatile oil ofpeppermint.

In certain embodiments, the vapor or aerosol is a vapor.

In certain embodiments, the vapor or aerosol is an aerosol.

In certain embodiments, the rebreathing device and its operation are asdescribed above.

In certain embodiments, the rebreathing device is a mask comprising asemi-porous substrate impregnated with the API, and the mask isconstructed and arranged to fit over nose, mouth, or both nose and mouthof the subject.

In certain embodiments, the mask is constructed and arranged to fit overthe nose of the subject.

In certain embodiments, the rebreathing device is breath-activated.

In certain embodiments, the vapor or aerosol is delivered to the airwaysby inhalation by the subject.

In certain embodiments, the subject is a human.

In accordance with each of the foregoing methods, a “therapeuticallyeffective amount” as used herein refers to an amount that is sufficientto achieve a desired therapeutic effect. The therapeutically effectiveamount can vary depending on such factors as the particular API, theparticular condition to be treated, and the age, size, and condition ofthe subject to be treated. The therapeutically effective amount can alsovary depending on the particular arrangement of the rebreathing deviceand the duration of treatment. A person of ordinary skill will be ableto determine what is a therapeutically effective amount based on invitro data, small animal data, and routine optimization.

In general, a therapeutically effective amount of the API is about 1 μgto about 100 mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 10 μg to about 100mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 100 μg to about 100mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 1 mg to about 100mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 10 mg to about 100mg per kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 1 μg to about 10 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 10μg to about 10 mg per kilogram of body weight. In certain embodiments,the therapeutically effective amount of the API is about 100 μg to about10 mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 1 mg to about 10 mgper kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 1 μg to about 1 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 10μg to about 1 mg per kilogram of body weight. In certain embodiments,the therapeutically effective amount of the API is about 100 μg to about1 mg per kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 1 μg to about 0.1 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 10μg to about 0.1 mg per kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 2.5 μg to about 100 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 25μg to about 100 mg per kilogram of body weight. In certain embodiments,the therapeutically effective amount of the API is about 250 μg to about100 mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 2.5 mg to about 100mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 25 mg to about 100mg per kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 2.5 μg to about 10 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 25μg to about 10 mg per kilogram of body weight. In certain embodiments,the therapeutically effective amount of the API is about 250 μg to about10 mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 2.5 mg to about 10mg per kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 2.5 μg to about 1 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 25μg to about 1 mg per kilogram of body weight. In certain embodiments,the therapeutically effective amount of the API is about 250 μg to about1 mg per kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 2.5 μg to about 0.1 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 25μg to about 0.1 mg per kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 5 μg to about 100 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 50μg to about 100 mg per kilogram of body weight. In certain embodiments,the therapeutically effective amount of the API is about 500 μg to about100 mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 5 mg to about 100mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 50 mg to about 100mg per kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 5 μg to about 10 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 50μg to about 10 mg per kilogram of body weight. In certain embodiments,the therapeutically effective amount of the API is about 500 μg to about10 mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 5 mg to about 10 mgper kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 5 μg to about 1 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 50μg to about 1 mg per kilogram of body weight. In certain embodiments,the therapeutically effective amount of the API is about 500 μg to about1 mg per kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 5 μg to about 0.1 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 50μg to about 0.1 mg per kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 7.5 μg to about 100 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 75μg to about 100 mg per kilogram of body weight. In certain embodiments,the therapeutically effective amount of the API is about 750 μg to about100 mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 7.5 mg to about 100mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 75 mg to about 100mg per kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 7.5 μg to about 10 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 75pig to about 10 mg per kilogram of body weight. In certain embodiments,the therapeutically effective amount of the API is about 750 μg to about10 mg per kilogram of body weight. In certain embodiments, thetherapeutically effective amount of the API is about 7.5 mg to about 10mg per kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 7.5 μg to about 1 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 75μg to about 1 mg per kilogram of body weight. In certain embodiments,the therapeutically effective amount of the API is about 750 μg to about1 mg per kilogram of body weight.

In certain embodiments, the therapeutically effective amount of the APIis about 7.5 μg to about 0.1 mg per kilogram of body weight. In certainembodiments, the therapeutically effective amount of the API is about 75μg to about 0.1 mg per kilogram of body weight.

The administering can be accomplished in a single dose or in a pluralityof doses. In certain embodiments, the administering is accomplished in asingle dose. In certain embodiments, the administering is accomplishedin two doses. In certain embodiments, the administering is accomplishedin three doses. In certain embodiments, the administering isaccomplished in four or more doses.

The administering can be one or more times a day. In certainembodiments, the administering is once a day. In certain embodiments,the administering is twice a day. In certain embodiments, theadministering is three times a day. In certain embodiments, theadministering is four times a day. In various additional embodiments,the administering is 5, 6, 7, 8, 9, 10, 11, or 12 times a day. Ingeneral, the frequency and spacing of dosing can be adapted to thesubject's symptoms and needs.

Kits

Also provided are kits useful in practicing the methods of theinvention. In an embodiment, a kit comprises an API as disclosed herein,and a semi-porous substrate. The semi-porous substrate is suitablyconstructed and arranged for application of the API to the semi-poroussubstrate.

In an embodiment, a kit comprises an API as disclosed herein, and arebreathing device. The rebreathing device is suitably constructed andarranged to receive the API and then deliver the API to the airways of asubject. In certain embodiments, the rebreathing device comprises asemi-porous substrate. In such embodiments, the rebreathing device issuitably constructed and arranged for application of the API to thesubstrate.

In certain embodiments, a kit comprises an API as disclosed herein, anda rebreathing device, wherein the rebreathing device is a maskcomprising a semi-porous substrate. The rebreathing device is suitablyconstructed and arranged to receive the API and then deliver the API tothe airways of a subject when placed over the nose or both the nose andmouth of the subject.

In each of the foregoing embodiments, the kit can further includeinstructions, written or otherwise, for how to use the components of thekit. For example, the instructions can direct a user how to assemble thecomponents, e.g., how to contact the API with the rebreathing device.The instructions can also direct a user how to use the assembled,activated rebreathing device to treat the condition to be treated, e.g.,how to use the assembled device to treat asthma.

The various components of the kit are typically provided in a tray orbox assembly, each component optionally provided in its own compartmentor packaging material. Each component optionally is provided in a sealedpackage, e.g., the API may be provided in a vial, pouch, or tube. A kitcan include components sufficient for a single use, or it can includecomponents sufficient for two or more uses.

I claim:
 1. A method of treating a respiratory disease or disorderinvolving the central airways, comprising administering to the centralairways of a subject in need thereof a vapor or aerosol comprising atherapeutically effective amount of an active pharmaceutical ingredient(API) selected from the group consisting of menthol, menthone,neomenthol, isomenthol, menthofuran, and any combination thereof,wherein the respiratory disease or disorder involving the centralairways is selected from the group consisting of bronchitis and arespiratory infection involving the central airways.
 2. The method ofclaim 1, wherein the API comprises menthol.
 3. The method of claim 1,wherein the API is provided as volatile oil of peppermint.
 4. The methodof claim 1, wherein the API is administered in conjunction with arebreathing device.
 5. The method of claim 4, wherein the rebreathingdevice comprises a semi-porous substrate impregnated with the API. 6.The method of claim 4, wherein the rebreathing device is a maskcomprising a semi-porous substrate impregnated with the API, and themask is constructed and arranged to fit over nose, mouth, or both noseand mouth of the subject.
 7. The method of claim 1, wherein the vapor oraerosol is delivered to the central airways by inhalation by thesubject.
 8. The method of claim 1, wherein the subject is a human.
 9. Amethod of treating allergic rhinitis, comprising administering to theupper airways of a subject in need thereof a vapor or aerosol comprisinga therapeutically effective amount of an active pharmaceuticalingredient (API) selected from the group consisting of menthol,menthone, neomenthol, isomenthol, menthofuran, and any combinationthereof, wherein the API is administered in conjunction with arebreathing device.
 10. The method of claim 9, wherein the API comprisesmenthol.
 11. The method of claim 9, wherein the API is provided asvolatile oil of peppermint.
 12. The method of claim 9, wherein therebreathing device comprises a semi-porous substrate impregnated withthe API.
 13. The method of claim 12, wherein the rebreathing device is amask comprising a semi-porous substrate impregnated with the API, andthe mask is constructed and arranged to fit over nose, mouth, or bothnose and mouth of the subject.
 14. The method of claim 9, wherein thevapor or aerosol is delivered to the upper airways by inhalation by thesubject.
 15. A method of treating cough, comprising administering to theairways of a subject in need thereof a vapor or aerosol comprising atherapeutically effective amount of an active pharmaceutical ingredient(API) selected from the group consisting of menthol, menthone,neomenthol, isomenthol, menthofuran, and any combination thereof,wherein the API is administered in conjunction with a rebreathingdevice.
 16. The method of claim 15, wherein the API comprises menthol.17. The method of claim 15, wherein the API is provided as volatile oilof peppermint.
 18. The method of claim 15, wherein the rebreathingdevice comprises a semi-porous substrate impregnated with the API. 19.The method of claim 18, wherein the rebreathing device is a maskcomprising a semi-porous substrate impregnated with the API, and themask is constructed and arranged to fit over nose, mouth, or both noseand mouth of the subject.
 20. The method of claim 15, wherein the vaporor aerosol is delivered to the airways by inhalation by the subject.